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A computational method for detection of ligand-binding proteins from dose range thermal proteome profiles

Detecting ligand-protein interactions in living cells is a fundamental challenge in molecular biology and drug research. Proteome-wide profiling of thermal stability as a function of ligand concentration promises to tackle this challenge. However, current data analysis strategies use preset threshol...

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Hauptverfasser: Kurzawa, Nils (Verfasst von) , Becher, Isabelle (Verfasst von) , Sridharan, Sindhuja (Verfasst von) , Franken, Holger (Verfasst von) , Mateus, André (Verfasst von) , Anders, Simon (Verfasst von) , Bantscheff, Marcus (Verfasst von) , Huber, Wolfgang (Verfasst von) , Savitski, Mikhail M. (Verfasst von)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 13 November 2020
In: Nature Communications
Year: 2020, Jahrgang: 11
ISSN:2041-1723
DOI:10.1038/s41467-020-19529-8
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-020-19529-8
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-020-19529-8
Volltext
Verfasserangaben:Nils Kurzawa, Isabelle Becher, Sindhuja Sridharan, Holger Franken, André Mateus, Simon Anders, Marcus Bantscheff, Wolfgang Huber & Mikhail M. Savitski
Beschreibung
Zusammenfassung:Detecting ligand-protein interactions in living cells is a fundamental challenge in molecular biology and drug research. Proteome-wide profiling of thermal stability as a function of ligand concentration promises to tackle this challenge. However, current data analysis strategies use preset thresholds that can lead to suboptimal sensitivity/specificity tradeoffs and limited comparability across datasets. Here, we present a method based on statistical hypothesis testing on curves, which provides control of the false discovery rate. We apply it to several datasets probing epigenetic drugs and a metabolite. This leads us to detect off-target drug engagement, including the finding that the HDAC8 inhibitor PCI-34051 and its analog BRD-3811 bind to and inhibit leucine aminopeptidase 3. An implementation is available as an R package from Bioconductor (https://bioconductor.org/packages/TPP2D). We hope that our method will facilitate prioritizing targets from thermal profiling experiments.
Beschreibung:Gesehen am 15.01.2021
Beschreibung:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-020-19529-8

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